1. Field of the Invention
This invention relates to anticancer therapy.
2. Description of the Related Art
The purpose of anticancer therapy is to prevent cancer cells from multiplying, invading, metastasizing, and ultimately killing their host organism, e.g. a human or other mammal. Because cell multiplication is a characteristic of many normal cells as well as cancer cells, most anticancer therapies also have toxic effects on normal cells, particularly those with a rapid rate of turnover, such as bone marrow and mucous membrane cells. The goal in selecting an effective anticancer therapy, therefore, is to find a therapy that has a marked growth inhibitory or controlling effect on the cancer cells and a minimal toxic effect on the host. In the most effective therapies, the agents used are capable not only of inhibiting but also eradicating all cancer cells while sufficiently preserving normal cells to permit the host to return to normal or at least satisfactory life function and quality. Anticancer therapies include classic chemotherapy with antiproliferative agents (typically, small molecules) that target all dividing cells; molecular targeted therapy designed to specifically target cancer cells, such as functional therapy designed to alter a molecular function in the cancer cells with gene therapy, antisense therapy, and drugs such as erlotinib hydrochloride, gefitinib, and imatinib mesylate, and phenotype-directed therapy designed to target the unique phenotype of cancer cells such as therapy with monoclonal antibodies, immunotoxins, radioimmunoconjugates, and cancer vaccines; biologic therapy with cytokines such as interleukin-2 and interferon-α; and radiotherapy.
However, although the first effective anticancer compounds were brought into clinical trials in the 1940's, initial therapeutic results were disappointing. Regressions of acute lymphocytic leukemia and adult lymphomas were obtained with single agents such as the nitrogen mustards, antifolates, corticosteroids, and vinca alkaloids, but responses were frequently partial and only of short duration; and relapse was associated with resistance to the original drug. Initial resistance to a given single agent (natural resistance) is frequent, and even initially responsive cancers frequently display acquired resistance after drug exposure, probably owing to selection of pre-existing resistant cancer cells from a heterogeneous population and possibly also owing to an increased rate of mutation to resistance. This is consistent with the clinical observation that, with few exceptions, cancers are cured only by combination therapy. Cancers are frequently characterized as being resistant (not showing a response during the initial course of therapy) or refractory (having shown an initial response, then relapsed, and not showing a response on a later course of therapy) to anticancer therapies. Resistance to one anticancer drug, e.g. a platinum anticancer compound such as cisplatin, is often associated with cross-resistance to other drugs of the same class, e.g. other platinum compounds. Multiple drug resistance, also called pleiotropic drug resistance, is a phenomenon where treatment with one drug confers resistance not only to that drug and others of its class but also to unrelated agents.
Anticancer therapies, especially chemotherapies, are frequently employed in combination, for several principal reasons. First, treatment with two or more non-cross-resistant therapies may prevent the formation of resistant clones; second, the combination of two or more therapies that are active against cells in different phases of growth (resting—G0, postmitotic—G1, DNA synthesis—S, premitotic—G2, and mitotic—M) may kill cells that are dividing slowly as well as those that are dividing actively and/or recruit cells into a more actively dividing state, making them more sensitive to many anticancer therapies; and third, the combination may create a biochemical enhancement effect by affecting different pathways or different steps in a single biochemical pathway. Particularly when the toxicities of the therapies are non-overlapping, two or more therapies may be employed in full or nearly full amounts, and the effectiveness of each therapy will be maintained in the combination; thus, myelosuppressive drugs may be supplemented by non-myelosuppressive drugs such as the vinca alkaloids, prednisone, and bleomycin; and combination chemotherapies have been developed for a number of cancers that are not curable with single agents. Combinations of two or more of chemotherapy, molecular targeted therapy, biologic therapy, and radiotherapy are also known and used. Although the existence of a wide variety of mechanistically distinct anticancer therapies suggests that non-cross-resistant therapies can be found, cancer cells are known to possess a variety of mechanisms that confer pleiotropic drug resistance. These mechanisms of resistance contribute to the failure of combination therapy to cure common cancers such as metastatic colon cancer and prostate cancer.
A disadvantage of virtually all anticancer therapies is the occurrence of side effects, undesired effects caused by the anticancer therapy on a patient being treated for a cancer. While some effects are minor in their effect on the physical health of the patient, such as alopecia (which is common in patients treated with platinum compounds, taxanes, and anthracyclines), most others such as nausea, vomiting, and neutropenia (also common in patients treated with platinum compounds) can have such an effect on the physical health of the patient that their occurrence limits the ability to treat the patient with the desired amount of the anticancer therapy and/or the willingness of the patient to undertake the anticancer therapy. Protective and adjunctive agents (as discussed in paragraph [0038] below) and antiemetics can be used to ameliorate some of the side effects of some anticancer therapies; however, in many instances, anticancer therapy is administered not at the amount that would be maximally effective against the cancer cells themselves, but in an amount at which the side effects of the therapy are tolerable or treatable, the maximum tolerated dose.
Discussions of anticancer chemotherapy and biologic therapy, and their side effects, and examples of suitable therapeutic protocols, may be found in such books as Cancer Chemotherapy and Biotherapy: Principles and Practice, 3rd ed. (2001), Chabner and Longo, eds., and Handbook of Cancer Chemotherapy, 6th ed. (2003), Skeel, ed., both from Lippincott Williams & Wilkins, Philadelphia, Pa., U.S.A.; and regimens for anticancer therapies, especially chemotherapies, may be found on Web sites such as those maintained by the National Cancer Institute (www.cancer.gov), the American Society for Clinical Oncology (www.asco.org), and the National Comprehensive Cancer Network (www.nccn.org).
Glutathione (GSH), in its reduced form, is a tripeptide of the formula: γ-L-Glu-L-Cys-Gly (SEQ ID No 1). Reduced glutathione has a central role in maintaining the redox condition in cells and is also an essential substrate for glutathione S-transferase (GST). GST exists in mammals as a superfamily of isoenzymes which regulate the metabolism and detoxification of foreign substances introduced into cells. In general, GST can facilitate detoxification of foreign substances (including anticancer drugs), but it can also convert certain precursors into toxic substances. The isoenzyme GST P1-1 is constitutively expressed in many cancer cells, such as ovarian, non-small cell lung, breast, colorectal, pancreatic, and lymphoma tissue (more than 75% of human tumor specimens from breast, lung, liver, and colorectal cancers are reported to express GST P1-1). It is frequently overexpressed in tumors following treatment with many chemotherapeutic agents, and is seen in cancer cells that have developed resistance to these agents.
U.S. Pat. No. 5,556,942 discloses compounds of the formula
and their amides, esters, and salts, where:L is an electron withdrawing leaving group;Sx is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S30 (C1-C6alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;each R1, R2 and R3 is independently H or a non-interfering substituent;n is 0, 1 or 2;Y is selected from the group consisting of
where m is 1 or 2; andAAc is an amino acid linked through a peptide bond to the remainder of the compound, and their syntheses.
The compounds of the patent are stated to be useful drugs for the selective treatment of target tissues which contain compatible GST isoenzymes, and simultaneously elevate the levels of GM progenitor cells in bone marrow. Disclosed embodiments for L include those that generate a drug that is cytotoxic to unwanted cells, including the phosphoramidate and phosphorodiamidate mustards.
One of the compounds identified in the patent has the formula
It is referred to in the patent as TER 286 and named as γ-glutamyl-α-amino-β-((2-ethyl-N,N,N,N-tetra(2′-chloro) ethylphosphoramidate) sulfonyl)propionyl-(R)-(−)phenylglycine. This compound, later referred to as TLK(286, has the CAS name L-γ-glutamyl-3-[[2-[[bis[bis(2-choroethyl)-amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanyl-2-phenyl-(2R)-glycine. As the neutral compound, its recommended International Nonproprietary Name is canfosfamide; and as its hydrochloride acid addition salt, its United States Adopted Name is canfosfamide hydrochloride. Canfosfamide and its salts are anticancer compounds that are activated by the actions of GST P1-1, and by GST A1-1, to release the cytotoxic phosphorodiamidate mustard moiety.
In vitro, canfosfamide has been shown to be more potent in the M6709 human colon carcinoma cell line selected for resistance to doxorubicin and the MCF-7 human breast carcinoma cell line selected for resistance to cyclophosphamide, both of which overexpress GST P1-1, over their parental cell lines; and in murine xenografts of M7609 engineered to have high, medium, and low levels of GST P1-1, the potency of canfosfamide hydrochloride was positively correlated with the level of GST P1-1 (Morgan et al., Cancer Res., 58:2568 (1998)).
Canfosfamide, as its hydrochloride salt, is currently being evaluated in multiple clinical trials for the treatment of ovarian, breast, non-small cell lung, and colorectal cancers. It has demonstrated significant single agent antitumor activity and improvement in survival in patients with non-small cell lung cancer and ovarian cancer, and single agent antitumor activity in colorectal and breast cancer. Evidence from in vitro cell culture and tumor biopsies indicates that canfosfamide is non-cross-resistant to platinum, paclitaxel, and doxorubicin (Rosario et al., Mol. Pharmacol., 58:167 (2000)), and also to gemcitabine. Patients treated with canfosfamide hydrochloride show a very low incidence of clinically significant hematological toxicity.
Other compounds specifically mentioned within U.S. Pat. No. 5,556,942 are TLK231 (TER 231), L-γ-glutamyl-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanyl-glycine, activated by GST M1a-1a; TLK(303 (TER 303), L-γ-glutamyl-3-[[2-[[bis[bis(2-chloroethyl)-amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanyl-2-phenyl-(2S)-alanine, activated by GST A1-1; TLK(296 (TER 296), L-γ-glutamyl-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-phenylalanyl-glycine, activated by GST P1-1; and TLK297 (TER 297), L-γ-glutamyl-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-phenylalanyl-2-phenyl-(2R)-glycine, and their salts.
The disclosure of U.S. Pat. No. 5,556,942, and the disclosures of other documents referred to in this application, are incorporated into this application by reference.
Anticancer therapies are steadily evolving, but it remains true that even the best current therapies are not always even initially effective and frequently become ineffective after treatment, and are frequently accompanied by significant side effects, so that improved anticancer therapies are constantly being sought.